According to the Centers for Disease Control (CDC) case definition, Chronic Fatigue Syndrome (CFS) is an illness of severe fatigue with defined associated symptoms that cannot be ascribed to any other pathologic condition. Although studies on CFS have increased in recent years, no unanimity of opinion regarding etiology has emerged. Several etiologies have been proposed, immunological, neuroendocrine, and autonomic, and yet no physiological mechanism has been consistently and uniquely related to CFS. It is probable that CFS encompasses sub-populations that share a common symptom profile yet are mediated by different factors. Neuropeptides such as neuropeptide Y (NPY) have long been proposed to play a role in the pathogenesis of inflammatory diseases. NPY is a 36 amino acid neuropeptide, which participates in the regulation of a large number of physiological and pathophysiological processes in the cardiorespiratory system, immune system, nervous system and endocrine system. In the periphery, NPY is concentrated in the sympathetic nerve endings and is released alone or with catecholamines. NPY receptors are present most cells of the immune system, including NK cells. NPY suppresses natural killer cell function (NKCC). Given the potential for adverse effects with a constant stimulus, down regulation mechanisms are essential for neuropeptides, including NPY. One regulator of NPY is dipeptidyl peptidase IV (CD26). Preliminary data from our lab indicate that CD26 concentrations on lymphocytes are abnormally low. The role of NPY in CFS is undefined. Our goal is to improve the understanding of CFS pathophysiology and to develop biomarkers useful in diagnosis, in defining subsets and in therapeutic trials. In this study, we will study one aspect of the neuroimmune relationship in CFS. Specific Aim 1 is to determine the extent to which patients, or a subset of patients who meet the CFS case definition have elevated NPY, as compared to healthy, sedentary controls. Specific Aim 2 is to determine the relationship of NPY to the cell surface concentration of (CD26) in patients with CFS as compared to controls. Specific Aim 3 is to define the relationship of NPY and CD26 to NKCC in CFS. Specific Aim 4 is to determine the relationship of NPY and CD26 to clinical severity in CFS patients. [unreadable] [unreadable] [unreadable]